A zebrafish model in which glucagon receptor (gcgr) signaling has been interrupted; the two gcgr genes (gcgra and gcgrb) which are co-orthologs of human GCGR were inactivated using transcription activator-like effector nuclease (TALEN) individually and then together. The robust alpha-cell hyperplasia in gcgra-/-;gcgrb-/- larvae provides a platform to screen for chemical and genetic suppressors, and ultimately to identify the stimulus of alpha-cell hyperplasia and its signaling mechanism.